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Patterns and Mechanisms of Sex Ratio Distortion in the Collaborative bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449644; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Patterns and Mechanisms of Sex Ratio Distortion in the 2 Collaborative Cross Mouse Mapping Population 3 4 5 Brett A. Haines*, Francesca Barradale†, Beth L. Dumont*,‡ 6 7 8 * The Jackson Laboratory, 600 Main Street, Bar Harbor ME 04609 9 † Department of Biology, Williams College, 59 Lab Campus Drive, Williamstown, MA 01267 10 11 ‡ Tufts University, Graduate School of Biomedical Sciences, 136 Harrison Ave, Boston MA 12 02111 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449644; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 13 Running Title: Sex Ratio Distortion in House Mice 14 15 Key words: sex ratio distortion, Collaborative Cross, intergenomic conflict, sex chromosomes, 16 ampliconic genes, Slx, Slxl1, Sly, Diversity Outbred, house mouse 17 18 Address for Correspondence: 19 20 Beth Dumont 21 The Jackson Laboratory 22 600 Main Street 23 Bar Harbor, ME 04609 24 25 P: 207-288-6647 26 E: [email protected] 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449644; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 27 ABSTRACT 28 29 In species with single-locus, chromosome-based mechanisms of sex determination, the laws of 30 segregation predict an equal ratio of females to males at birth. Here, we show that departures 31 from this Mendelian expectation are commonplace in the 8-way recombinant inbred 32 Collaborative Cross (CC) mouse population. More than one-third of CC strains exhibit significant 33 sex ratio distortion (SRD) at wean, with twice as many male-biased than female-biased strains. 34 We show that these pervasive sex biases persist across multiple breeding environments, are 35 stable over time, are not fully mediated by maternal effects, and are not explained by sex-biased 36 neonatal mortality. SRD exhibits a heritable component, but QTL mapping analyses and 37 targeted investigations of sex determination genes fail to nominate any large effect loci. These 38 findings, combined with the reported absence of sex ratio biases in the CC founder strains, 39 suggest that SRD manifests from multilocus combinations of alleles only uncovered in 40 recombined CC genomes. We speculate that the genetic shuffling of eight diverse parental 41 genomes during the early CC breeding generations led to the decoupling of sex-linked drivers 42 from their co-evolved suppressors, unleashing complex, multiallelic systems of sex 43 chromosome drive. Consistent with this interpretation, we show that several CC strains exhibit 44 copy number imbalances at co-evolved X- and Y-linked ampliconic genes that have been 45 previously implicated in germline genetic conflict and SRD in house mice. Overall, our findings 46 reveal the pervasiveness of SRD in the CC population and nominate the CC as a powerful 47 resource for investigating sex chromosome genetic conflict in action. 48 49 50 ARTICLE SUMMARY 51 We compiled breeding records from The Collaborative Cross (CC) mouse mapping population 52 to quantify the frequency and explore potential mechanisms of sex ratio distortion. Strikingly, 53 more than one-third of CC strains yield significantly sex-biased litters. These sex biases are not 54 mediated by environmental effects and are moderately heritable. We conclude that the 55 widespread sex ratio distortion in the CC manifests from multilocus permutations of selfish sex- 56 linked elements and suppressors that are only recovered in the recombinant CC strains. 57 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449644; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 58 INTRODUCTION 59 60 In species with single locus sex determination, Mendel’s rules of inheritance predict an equal 61 number of males and females at birth. However, departures from this idealized expectation are 62 common in nature. Many species can manipulate offspring sex ratios based on prevailing 63 environmental conditions (Hamilton 1967; Nager et al. 1999; West and Sheldon 2002), including 64 season (Drickamer 1990), maternal diet (Rosenfeld et al. 2003), and resource availability 65 (Douhard 2017). Additionally, increasing maternal stress loads lead to skewed sex ratios in 66 many mammals (Linklater 2007; Helle et al. 2008; Ideta et al. 2009; Ryan et al. 2012). 67 68 Beyond environmental influences, sex ratio biases can also arise from diverse genetic 69 mechanisms. At one extreme, a segregating X-linked recessive lethal allele will be 70 disproportionately associated with male lethality and distort the population sex ratio toward an 71 excess of females. Although selection should rapidly eliminate such a hypothetical variant from 72 the population, many mutations exhibit sex-specific phenotypic effects (Karp et al. 2017) and 73 could, therefore, contribute to sex biases in live birth ratios (e.g., McNairn et al. 2019). In 74 addition, prior work from diverse natural and laboratory model systems has demonstrated that 75 sex-linked selfish elements can drive sex ratio distortion (SRD) by promoting the transmission of 76 their resident chromosome at the expense of the other sex chromosome (Wood and Newton 77 1991; Seehausen et al. 1999; Cocquet et al. 2012; Unckless et al. 2015; Lindholm et al. 2016; 78 Helleu et al. 2016; Zanders and Unckless 2019; Courret et al. 2019). 79 80 Under most circumstances, the presence of an X-linked (or Y-linked) selfish element will impose 81 an intense selective pressure for the rapid emergence of a suppressor on the other sex 82 chromosome, thereby restoring a balanced population sex ratio. Consequently, at any given 83 point, a population is expected to be at or near sex ratio parity due to the action of counteracting 84 drive and suppressor elements. However, because different populations evolve independent 85 drive-suppressor systems, outcrossing can disrupt co-adapted systems of alleles to unmask the 86 presence of cryptic sex ratio distorters. Indeed, SRD is frequently observed in inter-population 87 (James and Jaenike 1990; Merçot et al. 1995), intersubspecific (Macholán et al. 2008; Phadnis 88 and Orr 2009; Good et al. 2010; Cocquet et al. 2012; Kruger et al. 2019), and interspecific 89 hybrids (Dermitzakis et al. 2000; Tao et al. 2001). SRD is also typically associated with reduced 90 fertility (Phadnis and Orr 2009; Cocquet et al. 2010, 2012; Zanders and Unckless 2019), 91 implying that selfish drive elements often impose a fitness cost. 92 93 The house mouse (Mus musculus) sex chromosomes are crucibles of historical genetic conflict 94 between feuding drive elements on the X and Y. More than 90% of the house mouse Y 95 chromosome is comprised of ampliconic genes with X-linked homologous partners that are 96 theorized to reflect historical bouts of driver-suppressor evolution (Mueller et al. 2008; Soh et al. 97 2014). One such family includes the SYCP3-like gene family members, Slx, Slxl1, and Sly, 98 which are present at upwards of 50-100 copies per genome (Scavetta and Tautz 2010; Morgan 99 and Pardo-Manuel de Villena 2017). The Y-linked gene Sly and its X-linked homologs Slx and 100 Slxl1 are selfish drive elements that promote the transmission of their parent chromosome, 101 although the molecular mechanisms by which this distortion is rendered are not fully 102 understood. Knockdown or deletion of Sly results in over-transmission of the X-chromosome 103 and female biased-litters (Conway et al. 1994; Cocquet et al. 2009). Conversely, knockdown or 104 deletion of Slx/Slxl1 yields male-biased litters (Cocquet et al. 2012; Kruger et al. 2019). 105 Although there are striking differences in Slx/Slxl1 and Sly copy number among house mouse 106 subspecies, the ratio of X- to Y-linked copies within subspecies has been maintained in 107 stochiometric balance over evolutionary time, presumably as a result of selection for balanced 108 sex chromosome transmission (Scavetta and Tautz 2010; Morgan and Pardo-Manuel de Villena 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449644; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 109 2017). As expected, experimental crosses between subspecies and wild-caught intersubspecific 110 F1 house mouse hybrids frequently sire sex-biased litters (Macholán et al. 2008; Good et al. 111 2010; Turner et al. 2012). 112 113 Regardless of whether it emerges from environmental or genetic causes, SRD imposes 114 profound impacts on populations. Departure from a 1:1 sex ratio can influence the rate of 115 population growth, modulate the degree of mate competition, and even modify life-history 116 trajectories (Hamilton 1967; Le Galliard et al.
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